Polymers have important and wide-ranging applications. For example, orthopedic repairs, prosthesis implantation, soft tissue healing, sutures, and timed release of drugs all utilize polymers. Polyethylene is often used in joint replacements. Ligament and tendon repairs may employ polytetrafluoroethylene (PTFE, Teflon®) or condensation polymers (Dacron). Catheters may be made of PTFE or polyurethanes. Skin repair templates may use silicone and collagen. Polymethylmethacrylate (PMMA) is used for bone cement and replacement eye lenses. Similarly, dental cements are made from acrylics polymers (polyacrylic acid, PAA) cross-linked with calcium or zinc.
Despite these advances in biomaterial development, significant need for new compositions persists. Surgical adhesives, non-fouling implant surfaces, and scaffolds for tissue engineering are all applications for which improved compositions are still very much required.
Biological environments tend to be wet, contain large amounts of possible foulants (e.g., proteins, polysaccharides, cells), and may impart large mechanical stresses. In the case of surgical adhesives, for example, a suitable composition may have the following qualities: the ability to set in wet environments, create strong bonds with both soft tissue and hard bone, cure on a reasonable time scale, be convenient to work with, and be biocompatible. At this time, no available composition meets all these requirements well.
The two most commonly used surgical adhesives are fibrin and the cyanoacrylates. Fibrin is a two tube sealant comprised of fibrinogen and thrombin, essentially making a blood clot upon mixing. Biocompatibility is excellent, but bond strengths are weak and the composition is difficult to handle. The cyanoacrylates (e.g., ethylcyanoacrylate, “Super Glue”) can make strong bonds to tissue, but the cured adhesive is brittle and suffers from induction of acute inflammatory responses. In general, compositions like cyanoacrylates that are based upon reactive monomers, ready to polymerize after application to a surface, may not be suitable for biomedical applications. The reactive nature of such monomers tends to result in toxicity.
The oral environment is particularly problematic for adhesion. Mechanical stresses, a changing environment, and high levels of bacteria all challenge adhesion to teeth. Current dental cements are based upon zinc phosphate, zinc polyacrylic acid (PAA), or a glass ionomer consisting of a polycarboxylate (e.g., PAA) with an aluminosilicate. Although the biocompatibility and physical properties of these cements are good, they do not seal sufficiently well to teeth. Microleakage also is common and often leads to secondary caries and cement failure. Similar problems can arise with skeletal hard connective tissue repaired by use of ceramics and glasses (e.g., alumina, silica, hydroxyapatite). Here too, obtaining a good bond to the surface has proven difficult. Failure at the biomaterial-tissue interface is common.
Desirable medical adhesives and cements may be either degradable or permanent, depending upon the application. A soft tissue adhesive, for example, may be degraded after complete healing. For a bone cement, by contrast, permanent attachment is typically required.
In general, when two surfaces are in contact and placed under deformation, a modulus mismatch may yield high levels of interfacial stress. For example, attaching a soft tissue to a harder bone, a desirable adhesive may provide a gradient of moduli spanning the range from one surface to the next, in order to minimize interfacial stresses. Indeed, a significant problem with current polymethyl methacrylate (PMMA) bone cements is this modulus mismatch. For example, PMMA cements may be too hard, put stress on the interface with bone, and wear out.
At this time, no synthetic adhesive or cement can set in a wet environment, form strong bonds, provide a suitable modulus match to the surrounding tissue, and is biocompatible. Furthermore, new compositions are still required for bone and dental cements, nonfouling surfaces, controlled drug release, and tissue engineering scaffolds. These properties may also be desirable to applications in industry, scientific research, and consumer products, among other things.
Novel adhesive mechanisms may be generated by synthetically mimicking mechanisms used in nature by, for example but not limited to, barnacles, marine mussels, oysters, giant clams, starfish, sea cucumbers, limpets, soft coral, kelp, etc.
Barnacles and marine mussels are examples of animals able to affix themselves to nearly any surface, including polytetrafluoroethylene (PTFE, Teflon®). In order to set in wet environments, these organisms may apply proteins to surfaces of interest. Extensive cross-linking of the proteins may yield cured adhesives or cements. Although the exact nature of such protein-protein interactions is not yet known, the unusual amino acid 3,4-dihydroxyphenylalanine (DOPA) may be central to curing of mussel adhesive proteins. Cross-linking of DOPA-containing proteins may be a result of chemical oxidation, enzymatic oxidation, or metal chelation followed by radical generation.

Mussels may use iron for protein cross-linking and adhesive formation. More specifically, the iron in mussel adhesive may be bound by three DOPA residues, as shown in FIG. 1.
Oxygen may then react with this iron center to yield a protein based radical. Subsequent radical-radical coupling to further cross-link the composition, as well as radical surface coupling to create adhesive bonds, may then follow. Formation of these radicals may proceed by a mechanism similar to that proposed for the intradiol catechol dioxygenase enzymes. An Fe3+-DOPA may undergo valence tautomerism to Fe2+ semiquinone followed by O2 reaction with the semiquinone ligand. The radical species may be reactive given that it is short lived. Radical species may be present in barnacle cement. Thus radicals may be important intermediates in marine biomaterial generation.
Expression of DOPA-containing proteins has proven difficult. Enzymatic oxidation of tyrosine containing synthetic polypeptides may yield DOPA-containing products. Long polypeptides with DOPA may also be directly prepared. In general, however, proteins and polypeptides with DOPA residues may be impractical to products on a large scale and prohibitively expensive.